Studies of T cell activation of normal murine T cell clones of the T(H)1 type have shown that two signals are required to stimulate the cells to make interleukin 2 and divide. One signal is given through the antigen-specific receptor that is uniquely expressed on each clone. The other signal is called costimulation and is delivered through a different receptor that has not yet been characterized. Signal 1 in the absence of signal 2 induces a state of hyporesponsiveness in the T cell clone known as clonal anergy. In this state, the cell fails to make significant amounts of interleukin-2 when restimulated with both signals 1 and 2. During the past year, the reasons for this failure to make IL-2 were examined at the molecular level. Although signaling through tile antigen receptor was found to be normal, as assessed by increases in intracellular calcium and protein kinase C activation, steady state levels of IL-2 mRNA were decreased 20 to 50-fold. Other lymphokines were also affected but not as profoundly. Interleukin 3 production in response to stimulation was down 8-fold and gamma interferon and tumor necrosis factor production were down 3-fold. In an attempt to extend our observations on T(H)1 clones to other T cell subpopulations, we tried to induce clonal allergy in T(H)2 T(H)0 and freshly isolated T lymphocytes from immunized mice. Three bona fide T(H)2 clones could not be anergized with any of three techniques used to anergize T(H)1 clones. In contrast, two T(H)0 clones could be anergized. The common theme appears to be whether the T cell clone depends on IL-2 for its autocrine growth. T(H)1 and T(H)0 clones, which utilize IL-2, can be anergized, whereas T(H)2 cells, which utilize different growth factors, cannot. Finally, freshly isolated T cells behaved in an anomalous manner. These cells could be anergized when exposed to the calcium ionophore, ionomycin, but not when stimulated with antigen on chemically-fixed presenting cells. The reason(s) for this last paradoxical set of results is still under investigation.